Dosing: Adult For the different doses, film-coated tablets containing 5 mg and 7.5 mg ivabradine are available. Treatment of coronary artery diseaseThe usual recommended starting dose of ivabradine is 5 mg twice daily. After three to four weeks of treatment, the dose may be increased to 7.5 mg twice daily depending on the therapeutic response. If, during treatment, heart rate decreases persistently below 50 beats per minute (bpm) at rest or the patient experiences symptoms related to bradycardia such as dizziness, fatigue or hypotension, the dose must be titrated downward including the possible dose of 2.5 mg twice daily (one half 5 mg tablet twice daily). Treatment must be discontinued if heart rate below 50 bpm or symptoms of bradycardia persist .Treatment of chronic heart failure The treatment has to be initiated only in patient with stable heart failure. It is recommended that the treating physician should be experienced in the management of chronic heart failure.The usual recommended starting dose of ivabradine is 5 mg twice daily. After two weeks of treatment, the dose can be increased to 7.5 mg twice daily if resting heart rate is persistently above 60 bpm or decreased to 2.5 mg twice daily (one half 5 mg tablet twice daily) if resting heart rate is persistently below 50 bpm or in case of symptoms related to bradycardia such as dizziness, fatigue or hypotension. If heart rate is between 50 and 60 bpm, the dose of 5 mg twice daily should be maintained. If during treatment, heart rate decreases persistently below 50 beats per minute (bpm) at rest or the patient experiences symptoms related to bradycardia, the dose must be titrated downward to the next lower dose in patients receiving 7.5 mg twice daily or 5 mg twice daily. If heart rate increases persistently above 60 beats per minute at rest, the dose can be up titrated to the next upper dose in patients receiving 2.5 mg twice daily or 5 mg twice daily.Treatment must be discontinued if heart rate remains below 50 bpm or symptoms of bradycardia persist

Dosing: PediatricThe safety and efficacy of ivabradine in children aged below 18 years have not yet been established.No data are available.

Dosing: Geriatric In patients aged 75 years or more, a lower starting dose should be considered for these patients (2.5 mg twice daily i.e. one half 5 mg tablet twice daily) before up-titration if necessary.

Dosing: Renal Impairment No dose adjustment is required in patients with renal insufficiency and creatinine clearance above 15 ml/min.No data are available in patients with creatinine clearance below 15 ml/min. Ivabradine should therefore be used with precaution in this population.Dosing: Hepatic Impairment No dose adjustment is required in patients with mild hepatic impairment. Caution should be exercised when using ivabradine in patients with moderate hepatic impairment. Ivabradine is contra-indicated for use in patients with severe hepatic insufficiency, since it has not been studied in this population and a large increase in systemic exposure is anticipated .

Use

Treatment of coronary artery diseaseSymptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm. Ivabradine is indicated:- in adults unable to tolerate or with a contra-indication to the use of beta-blockers- or in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose and whose heart rate is > 60 bpm.Treatment of chronic heart failureIvabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated

Adverse Reactions

Ivabradine has been studied in clinical trials involving nearly 14,000 participants. The most common adverse reactions with ivabradine, luminous phenomena (phosphenes) and bradycardia, are dose dependent and related to the pharmacological effect of the medicinal product.Tabulated list of adverse reactionsThe following adverse reactions have been reported during clinical trials and are ranked using the following frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

System Organ Class

Frequency

Preferred Term

Blood and lymphatic system disorders

Uncommon

Eosinophilia

Metabolism and nutrition disorders

Uncommon

Hyperuricaemia

Nervous system disorders

Common

Headache, generally during the first month of treatment

Dizziness, possibly related to bradycardia

Uncommon*

Syncope, possibly related to bradycardia

Eye disorders

Very common

Luminous phenomena (phosphenes)

Common

Blurred vision

Ear and labyrinth disorders

Uncommon

Vertigo

Cardiac disorders

Common

Bradycardia

AV 1st degree block (ECG prolonged PQ interval)

Ventricular extrasystoles

Uncommon

Palpitations, supraventricular extrasystoles

Very rare

Atrial fibrillation

AV 2nd degree block, AV 3rd degree block

Sick sinus syndrome

Vascular disorders

Common

Uncontrolled blood pressure

Uncommon*

Hypotension, possibly related to bradycardia

Respiratory, thoracic and mediastinal disorders

Uncommon

Dyspnoea

Gastrointestinal disorders

Uncommon

Nausea

Constipation

Diarrhoea

Skin and subcutaneous tissue disorders

Uncommon*

Angioedema

Rash

Rare*

Erythema

Pruritus

Urticaria

Musculoskeletal and connective tissue disorders

Uncommon

Muscle cramps

General disorders and administration site conditions

Uncommon*

Asthenia, possibly related to bradycardia

Fatigue, possibly related to bradycardia

Rare*

Malaise, possibly related to bradycardia

Investigations

Uncommon

Elevated creatinine in blood

ECG prolonged QT interval

* Frequency calculated from clinical trials for adverse events detected from spontaneous reportDescription of selected adverse reactionsLuminous phenomena (phosphenes) were reported by 14.5% of patients, described as a transient enhanced brightness in a limited area of the visual field. They are usually triggered by sudden variations in light intensity. The onset of phosphenes is generally within the first two months of treatment after which they may occur repeatedly. Phosphenes were generally reported to be of mild to moderate intensity. All phosphenes resolved during or after treatment, of which a majority (77.5%) resolved during treatment. Fewer than 1% of patients changed their daily routine or discontinued the treatment in relation with phosphenes.Bradycardia was reported by 3.3% of patients particularly within the first 2 to 3 months of treatment initiation. 0.5% of patients experienced a severe bradycardia below or equal to 40 bpm.

Special warningsCardiac arrhythmiasIvabradine is not effective in the treatment or prevention of cardiac arrhythmias and likely loses its efficacy when a tachyarrhythmia occurs (eg. ventricular or supraventricular tachycardia). Ivabradine is therefore not recommended in patients with atrial fibrillation or other cardiac arrhythmias that interfere with sinus node function.It is recommended to regularly clinically monitor ivabradine treated patients for the occurrence of atrial fibrillation (sustained or paroxysmal), which should also include ECG monitoring if clinically indicated (e.g. in case of exacerbated angina, palpitations, irregular pulse). The risk of developing atrial fibrillation may be higher in chronic heart failure patients treated with ivabradine. Atrial fibrillation has been more common in patients using concomitantly amiodarone or potent class I anti-arrhythmics. Chronic heart failure patients with intraventricular conduction defects (bundle branch block left, bundle branch block right) and ventricular dyssynchrony should be monitored closely.Use in patients with AV-block of 2nd degreeIvabradine is not recommended in patients with AV-block of 2nd degree.Use in patients with a low heart rateIvabradine must not be initiated in patients with a pre-treatment resting heart rate below 60 beats per minute If, during treatment, resting heart rate decreases persistently below 50 bpm or the patient experiences symptoms related to bradycardia such as dizziness, fatigue or hypotension, the dose must be titrated downward or treatment discontinued if heart rate below 50 bpm or symptoms of bradycardia persist .Combination with calcium channel blockersConcomitant use of ivabradine with heart rate reducing calcium channel blockers such as verapamil or diltiazem is not recommended . No safety issue has been raised on the combination of ivabradine with nitrates and dihydropyridine calcium channel blockers such as amlodipine. Additional efficacy of ivabradine in combination with dihydropyridine calcium channel blockers has not been established Chronic heart failure Heart failure must be stable before considering ivabradine treatment. Ivabradine should be used with caution in heart failure patients with NYHA functional classification IV due to limited amount of data in this population.StrokeThe use of ivabradine is not recommended immediately after a stroke since no data is available in these situations.Visual functionIvabradine influences on retinal function . To date, there is no evidence of a toxic effect of ivabradine on the retina, but the effects of long-term ivabradine treatment beyond one year on retinal function are currently not known. Cessation of treatment should be considered if any unexpected deterioration in visual function occurs. Caution should be exercised in patients with retinitis pigmentosa.Precautions for usePatients with hypotensionLimited data are available in patients with mild to moderate hypotension, and ivabradine should therefore be used with caution in these patients. Ivabradine is contra-indicated in patients with severe hypotension (blood pressure < 90/50 mmHg) .Atrial fibrillation - Cardiac arrhythmiasThere is no evidence of risk of (excessive) bradycardia on return to sinus rhythm when pharmacological cardioversion is initiated in patients treated with ivabradine. However, in the absence of extensive data, non urgent DC-cardioversion should be considered 24 hours after the last dose of ivabradine.Use in patients with congenital QT syndrome or treated with QT prolonging medicinal productsThe use of ivabradine in patients with congenital QT syndrome or treated with QT prolonging medicinal products should be avoided . If the combination appears necessary, close cardiac monitoring is needed. Heart rate reduction, as caused by ivabradine, may exacerbate QT prolongation, which may give rise to severe arrhythmias, in particular Torsade de pointes.Hypertensive patients requiring blood pressure treatment modifications.In the SHIFT trial more patients experienced episodes of increased blood pressure while treated with ivabradine (7.1%) compared to patients treated with placebo (6.1%). These episodes occurred most frequently shortly after blood pressure treatment was modified, were transient, and did not affect the treatment effect of ivabradine. When treatment modifications are made in chronic heart failure patients treated with ivabradine blood pressure should be monitored at an appropriate interval .ExcipientsSince tablets contain lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Interactions

This drug should not be used with the following medications because very serious, possibly fatal interactions may occur: Ketoconazole itraconazole clarithromycin erythromycin Diltiazem verapamil If you are currently using any of these medications, tell your doctor or pharmacist before starting ivabradine. Fluconazole rifampicin barbiturates grapefruit juice phenytoin St John's wort quinidine disopyramide ibutilide Sotalol amiodarone

Pregnancy

Pregnancy Implications There are no or limited amount of data from the use of ivabradine in pregnant women. Studies in animals have shown reproductive toxicity. These studies have shown embryotoxic and teratogenic effects . The potential risk for humans is unknown. Therefore, ivabradine is contra-indicated during pregnancy

Lactation

Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contra-indicated during breast-feeding .

Mechanism of Action

Ivabradine is a pure heart rate lowering agent, acting by selective and specific inhibition of the cardiac pacemaker If current that controls the spontaneous diastolic depolarisation in the sinus node and regulates heart rate. The cardiac effects are specific to the sinus node with no effect on intra-atrial, atrioventricular or intraventricular conduction times, nor on myocardial contractility or ventricular repolarisation.Ivabradine can interact also with the retinal current Ih which closely resembles cardiac If. It participates in the temporal resolution of the visual system, by curtailing the retinal response to bright light stimuli. Under triggering circumstances (e.g. rapid changes in luminosity), partial inhibition of Ih by ivabradine underlies the luminous phenomena that may be occasionally experienced by patients. Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field

Pharmacodynamics / Kinetics

Under physiological conditions, ivabradine is rapidly released from tablets and is highly water-soluble (>10 mg/ml). Ivabradine is the S-enantiomer with no bioconversion demonstrated in vivo. The N-desmethylated derivative of ivabradine has been identified as the main active metabolite in humans.Absorption and bioavailability Ivabradine is rapidly and almost completely absorbed after oral administration with a peak plasma level reached in about 1 hour under fasting condition. The absolute bioavailability of the film-coated tablets is around 40%, due to first-pass effect in the gut and liver. Food delayed absorption by approximately 1 hour, and increased plasma exposure by 20 to 30 %. The intake of the tablet during meals is recommended in order to decrease intra-individual variability in exposure .Distribution Ivabradine is approximately 70% plasma protein bound and the volume of distribution at steady state is close to 100 l in patients. The maximum plasma concentration following chronic administration at the recommended dose of 5 mg twice daily is 22 ng/ml (CV=29%). The average plasma concentration is 10 ng/ml (CV=38%) at steady state.Biotransformation Ivabradine is extensively metabolised by the liver and the gut by oxidation through cytochrome P450 3A4 (CYP3A4) only. The major active metabolite is the N-desmethylated derivative (S 18982) with an exposure about 40% of that of the parent compound. The metabolism of this active metabolite also involves CYP3A4. Ivabradine has low affinity for CYP3A4, shows no clinically relevant CYP3A4 induction or inhibition and is therefore unlikely to modify CYP3A4 substrate metabolism or plasma concentrations. Inversely, potent inhibitors and inducers may substantially affect ivabradine plasma concentrations .Elimination Ivabradine is eliminated with a main half-life of 2 hours (70-75% of the AUC) in plasma and an effective half-life of 11 hours. The total clearance is about 400 ml/min and the renal clearance is about 70 ml/min. Excretion of metabolites occurs to a similar extent via faeces and urine. About 4% of an oral dose is excreted unchanged in urine.